Hyperlipemia has been known to be a state in which levels of neutral fat and cholesterol in blood are higher than normal levels. Hyperlipemia is subjected to the treatment because it is a major risk factor of ischemic diseases. Hyperlipemia has been also known to cause arteriosclerosis. In particular, it is effective for the prevention and the treatment of arteriosclerosis to lower the level of cholesterol in the blood. The arteriosclerosis has been known to cause myocardial infarction, cerebral thrombosis, peripheral arterial obstruction and arteriosclerotic obliteration. Syndrome X has been proposed by Reaven et al. (e.g., see Non-patent Document 1 [Reaven et al., “Diabetes”, 37:1595-1607, 1988]), and is a multiple risk factor syndrome in which the arteriosclerosis occurs by accumulating the multiple risk factors of hyperinsulinism, hyperlipemia, hypertension and impaired glucose tolerance in an individual body although each factor is not pathogenic when each factor is present independently. It has been believed that a cholesterol lowering agent is effective for the prevention or the treatment of these diseases (e.g., see Non-patent Document 2 [“Nippon Rinsho, Koshikessho Jo (Japanese Journal of Clinical Medicine, Hyperlipemia Volume 1)” ISSN 0047-1852]).
Examples of therapeutic agents for hyperlipemia which are currently commercially available may include 3-hydroxy-3-methylglutaryl coenzyme A (abbreviated hereinbelow as HMG-CoA) reductase inhibitors and bile acid absorbers (anion exchange resin drug). These are used particularly for the prevention or the treatment of hypercholesterolemia and arteriosclerosis in hyperlipemia. These are further used for the prevention or the treatment of myocardial infarction, cerebral thrombosis, peripheral arterial obstruction and arteriosclerotic obliteration caused by hypercholesterolemia and arteriosclerosis.
Other therapeutic agents for hyperlipemia may include anti-oxidants, nicotinic acid derivatives and cholesterol absorption inhibitors. Fibrate drugs which act upon α-receptor of peroxisome proliferator-activated receptors (abbreviated hereinbelow as PPAR) are also included in this category because they have neutral fat lowering and cholesterol lowering effects.
The HMG-CoA reductase inhibitors, which are generally referred to as statins, inhibit a cholesterol synthesis pathway and exhibit the strong cholesterol lowering effect, but rarely cause a severe side effect such as rhabdomyolysis and also cause myopathy and hepatic disorders in some cases. Thus, statins are generally used below the excessive amount.
Therefore, when the use of statin alone can not lower the level of cholesterol sufficiently, co-administration with another therapeutic agent for hyperlipemia having a different action mechanism is considered for lowering cholesterol to a target level. However, when considering the combination with the fibrate drug for an example, the fibrate drug itself also causes rhabdomyolysis in some cases. Thus, the therapy by this combination is not usually used because of the higher risk of rhabdomyolysis.
The combination of the statin drugs and the anion exchange resin drug augments the cholesterol lowering effect compared with the use of statin alone. Thus, when the use of statin alone does not lower to the target level, this combination can be used. However, it is necessary to take the bile acid absorber in a large amount in order to obtain a commeasurable drug effect. Thus, the bile acid absorber has difficulty upon taking and largely affects gastrointestinal tract to cause constipation. In addition, the anion exchange resin drug also absorbs vitamins A, D, E and K or simultaneously administered anionic drugs. Considering these effects, the combination of the HMG-CoA reductase inhibitor with the bile acid absorber such as anion exchange resin drug is not the best mode of the treatment which patients should receive.
The combination of the cholesterol absorption inhibitor with the HMG-CoA reductase inhibitor is effective. However, the cholesterol absorption inhibitor is also incorporated in the body and metabolized in liver. Thus the cholesterol absorption inhibitor can not be administered to a patient having a disease in liver. The combination of the cholesterol absorption inhibitor with the fibrate drugs is not usually used because a drug interaction is concerned.
Additional examples of drugs capable of treating hyperlipemia may include a cholesterol ester transfer protein (abbreviated hereinbelow as CETP) inhibitor, nicotinic acid and derivatives thereof, an acylcoenzyme A: cholesterol acetyltransferase (abbreviated hereinbelow as ACAT) inhibitor and a microsomal transfer protein (abbreviated hereinbelow as MTP) inhibitor. They are commonly absorbed in the body to exert medicinal effects, and thus the drug interaction is likely to occur when combined with the other cholesterol lowering drug such as HMG-CoA reductase inhibitor.
It is generally effective in the treatment to combine the drugs each having different action mechanisms for exerting the effect over a certain level. However, when each drug is absorbed to plasma proteins or when a drug metabolism process is shared by the combined drugs, the risk of side effect occurrence becomes high because of more rapid increase of drug concentrations in blood and larger effect on tissues than those which occur with the use of a single drug. In addition, in the case of the patient having a plurality of risk factors for the coronary artery disease, a plurality of drugs are often prescribed for coping with respective risk factors. For example, in the cases of the combination of hyperlipemia and hypertension and the combination of hyperlipemia and diabetes, the therapeutic drug for hyperlipemia is combined with the therapeutic drug for another disease. At that time, the interaction between the drugs must be sufficiently considered.